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Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 16, 2010
The human immunodeficiency virus gp120 binding site on CD4: delineation by quantitative equilibrium and kinetic
U Moebius1, L K Clayton, S Abraham
1Laboratory of Immunobiology, Dana Farber Cancer Institute, Boston, Massachusetts.
Insights
Researchers identified key residues on CD4 critical for binding human immunodeficiency virus gp120. This finding is crucial for developing new HIV therapies by understanding the virus-receptor interaction.
Area of Science:
- Structural Biology
- Virology
- Immunology
Background:
- The CD4 molecule on T-helper cells is the primary receptor for the human immunodeficiency virus (HIV).
- The HIV envelope glycoprotein gp120 mediates viral entry by binding to CD4.
- Understanding the precise binding interface is essential for therapeutic intervention.
Purpose of the Study:
- To map the specific amino acid residues within the CD4 molecule that constitute the binding site for HIV gp120.
- To characterize the contribution of individual residues to the binding affinity and kinetics.
Main Methods:
- Utilized atomic structure of a CD4 fragment to guide mutant design.
- Employed equilibrium and kinetic analyses to assess gp120 binding to CD4 mutants.
- Site-directed mutagenesis of key CD4 residues.
Main Results:
- Identified a binding site on the C" edge of the CD4 V-like domain (approx. 900 A2).
- Key residues include hydrophobic Phe43 and positively charged Lys29, Lys35, Lys46, and Arg59.
- Phe43 substitution dramatically reduced gp120 affinity (>500-fold); charged residues contributed 7-50-fold.
- The CD4 binding site likely interacts with a conserved hydrophobic pocket on gp120.
Conclusions:
- The CD4-gp120 interaction involves specific hydrophobic and charged residues on CD4.
- This binding site overlaps with the binding region for Class II major histocompatibility complex (MHC).
- Knowledge of this interface is vital for designing effective CD4-gp120 interaction inhibitors.
Abstract:
The first immunoglobulin V-like domain of CD4 contains the binding site for human immunodeficiency virus gp120. Guided by the atomic structure of a two-domain CD4 fragment, we have examined gp120 interaction with informative CD4 mutants, both by equilibrium and kinetic analysis. The binding site on CD4 appears to be a surface region of about 900 A2 on the C" edge of the domain. It contains an exposed hydrophobic residue, Phe43, on the C" strand and four positively charged residues, Lys29, Lys35, Lys46, and Arg59, on the C, C', C", and D strands, respectively. Replacement of Phe43 with Ala or Ile reduces affinity for gp120 by more than 500-fold; Tyr, Trp, and Leu substitutions have smaller effects. The four positively charged side chains each make significant contributions (7-50-fold). This CD4 site may dock into a conserved hydrophobic pocket bordered by several negatively charged residues in gp120. Class II major histocompatibility complex binding includes the same region on CD4; this overlap needs to be considered in the design of inhibitors of the CD4-gp120 interaction.
